Processes for making porous implantable materials

ABSTRACT

Described herein are methods of making open celled foams including a matrix of interconnected spheres. The open celled foams are silicone based materials and can be used to coat implants, such as breast implants, and function to encourage tissue ingrowth and reduce capsular formation.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.13/012,991, filed Jan. 25, 2011, now issued U.S. Pat. No. 8,487,012,which claims priority to U.S. Provisional Patent Application No.61/299,218, filed on Jan. 28, 2010, the entire disclosure of which isincorporated herein by this specific reference.

FIELD OF THE INVENTION

The present invention relates to open celled foams and methods formaking and use of same.

BACKGROUND

Whether for cosmetic, aesthetic, or reconstructive purposes, soft tissueimplants have become commonplace in today's society. Despite theirgrowing popularity, a soft tissue implant can result, in some cases, incapsular contracture. Soon after an implant is placed into the body aninflammatory response begins to deposit collagen around the implant inthe form of a fibrous capsule. In most cases for larger smooth implantsthe fibrous capsule is comprised of highly aligned and organizedcollagen fibers. As the fibrous capsule matures, certain events maytrigger the differentiation of fibroblasts to a contractile phenotype,for example, myofibroblasts, and if the collagen fibers adjacent to theimplant are aligned, capsular contracture ensues.

Capsular contracture can be debilitating to a patient because ofdiscomfort or even pain, and can diminish the efficacy of the cosmeticor aesthetic results in both the look and feel of the implant.

Problems with capsular formation and contracture occur in many implanttypes such as pacemakers, dura mater substitutes, implantable cardiacdefibrillators as well as breast and other esthetic implants. Implantswith smooth surfaces in particular suffer most from capsular formationand contracture. Surface texturing has been shown to reduce capsularcontracture when compared to common smooth surface implants when theimplant is placed subglandularly.

Polyurethane textured coatings have been developed in an effort toreduce capsular formation and contracture. However, these coatings arebiodegradable, and will therefore, lose any potential efficacy once thepolyurethanes degrade. Also, some types of polyurethanes have been shownto degrade to potentially carcinogenic byproducts in vitro. Even furtherstill, the manufacturing of polyurethane foam coated implants isincreasingly complicated raising the cost of the resulting implant.

As such, there is a need in the art for textured implant coatings thatreduce or even eliminate capsular formation and contracture. The presentdescription fulfills this need in the art by providing coatings,implants including the coatings and methods of making and using thesame.

SUMMARY

Described herein are open celled foams including matrices ofinterconnected spheres. Also described herein are methods of making opencelled foams as well as methods of making composite members with opencelled foam coatings covering at least a portion of the compositemember's surface. Methods of using these foams are also described.

In one embodiment, the spheres comprise substantially pure silicone andhave a diameter of between about 10 μm and about 2,000 μm or about 25 μmand about 200 μm. The matrix of interconnected spheres can have atheoretical void space of about 50% to about 99%. In other embodiments,the theoretical void space is between about 60% and 88%. The matrix ofinterconnected spheres can have a physical void space of about 50% toabout 70%. The silicone used to make the foams can be, for example, aroom temperature vulcanizing (RTV) silicone or high temperaturevulcanizing (HTV) silicone.

Further, in one embodiment, soft tissue implants are describedcomprising a textured coating on at least a portion of the soft tissueimplant, the coating comprising a matrix of interconnected spheres, thespheres comprising substantially pure silicone wherein the matrix ofinterconnected spheres has a theoretical void space of about 50% toabout 99%. In another embodiment, the implant is a breast implant. Inother embodiments, the implant can be a pace maker lead, a medical port,catheter, dura mater substitutes, hernia meshes or the like.

In one embodiment described herein are processes for forming open celledfoams comprising the steps of: combining a first composition comprisinga first organic solvent and at least one extractable agent, and a secondcomposition comprising a second organic solvent and at least onesilicone matrix agent thereby forming a mixture, wherein the at leastone matrix agent is less than about 40% v/v of the mixture; agitatingthe mixture thereby forming an emulsion; and curing the emulsion therebyforming the open celled foam, wherein the matrix open celled foam has atheoretical void space of about 50% to about 99%.

In another embodiment, the first organic solvent and the second organicsolvent are the same or different and are selected from the groupconsisting of dichloromethane, water, xylene, acetone, methanol, methylacetate, hexane, benzene toluene, isopropyl alcohol, or other suitableprotic or aprotic solvent. In still another embodiment, curing stepfurther comprises heating the emulsion. In some embodiments, the processfurther comprises the step of casting the emulsion before the curingstep, in other embodiments the emulsion may be used in any otherconventional coating process, such as curtain coating, spray coating,dip coating, or the like.

In another example embodiment, the removable polymer is selected fromgroup consisting of polyethylene glycol, poly propylene glycol, polyacrylic acid, poly acrylamide, dextran, chitosan, alginate,carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol,polyvinyl pyrrolidone, or other aliphatic or aromatic polymers,co-polymers thereof, blends thereof or combinations thereof. A removablepolymer, can be soluble, or sublimable or degradable or a combinationthereof, wherein the processing thereof does not substantially affectthe silicone matrix).

In other embodiments, the process further comprises the step of dippinga soft tissue implant into the emulsion before the curing step. The softtissue implant can be, for example, a breast implant. In otherembodiments, the implant can be a pace maker lead, a medical port,catheter, dura mater substitutes, hernia meshes or the like.

In one embodiment described herein are implantable composite membershaving an external surface at least a portion of which is covered by anopen celled foam structure, the member made by the method comprising thesteps of: (a) providing an implantable shell; (b) providing an opencelled foam comprising a matrix of interconnected spheres, the spherescomprising substantially pure silicone, and wherein the matrix ofinterconnected spheres has a theoretical void space of about 50% toabout 99%; (c) applying a bonding substance to the open celled foamthereby forming a bondable open celled foam; (d) applying the bondableopen celled foam to at least a portion of the implantable shell; (e)curing the bonding substance; and (f) forming a composite materialhaving an external surface at least a portion of which is covered by anopen celled foam. Alternatively the bonding substance can be applied tothe device upon which the open cell foam will be laminated.

In another embodiment, the implantable shell is a breast implant. Instill other embodiments, the curing step further comprises heating theemulsion.

Further described herein are composite materials useful as a shell for aprosthesis having a surface as illustrated in any one of FIG. 9, FIG.10, FIG. 11, FIG. 12, FIG. 13, FIG. 14, FIG. 15, FIG. 16, FIG. 17 orFIG. 18.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary binary phase diagram for open celledfoams as described herein.

FIG. 2 illustrates a smooth implant with a formed capsule.

FIG. 3 illustrates another smooth implant with a formed capsule after1.5 months in a rat.

FIG. 4 illustrates an implant without sufficient pore size to allowsubstantial tissue ingrowth. Rather only a very fine layer of ingrowthis achieved.

FIG. 5 illustrates an implanted polyurethane foam.

FIG. 6 illustrates an open celled foam implant produced according to thepresent description without capsule formation.

FIG. 7 illustrates another open celled silicone foam implant producedaccording to the present description without capsule formation.

FIG. 8 illustrates a magnified image of open celled foam formulation F30from Table 1.

FIG. 9 illustrates a second magnified image of open celled foamformulation F30 from Table 1.

FIG. 10 illustrates a magnified image of open celled foam formulationF31 from Table 1.

FIG. 11 illustrates a magnified image of open celled foam formulationF31 from Table 1.

FIG. 12 illustrates a magnified image of a cross-sectional view of opencelled foam formulation F35 from Table 1.

FIG. 13 illustrates a magnified image of a bottom view of open celledfoam formulation F35 from Table 1.

FIG. 14 illustrates a magnified image of a top view of open celled foamformulation F35 from Table 1.

FIG. 15 illustrates a magnified image of open celled foam formulationF42 from Table 1 attached to a solid RTV silicone backing.

FIG. 16 illustrates a magnified image of open celled foam formulationF36 from Table 1 attached to a solid RTV silicone backing.

FIG. 17 illustrates a magnified image of a cross-sectional view of opencelled foam formulation F36 from Table 1.

FIG. 18 illustrates a magnified image of an open celled foam showingactual void space.

FIG. 19 illustrates a magnified image of another open celled foamshowing actual void space.

FIG. 20 illustrates a magnified image of an emulsion showing the sizedistribution of microspheres present therein.

FIG. 21 illustrates a magnified image of another emulsion showing thesize distribution of microspheres present therein.

DETAILED DESCRIPTION

Described herein are open celled foams including matrices ofinterconnected spheres. Also described herein are methods of making opencelled foams as well as making composite members with open celled foamcoatings covering at least a portion of the composite member's surface.

The foams described herein can be coated on a composite member such asan implant. The implant can be a soft tissue implant, an artificialbone, a joint implant, a bone screw, an implantable medical device, or acombination thereof. In one embodiment, the soft tissue implant isselected from breast implants, cheek implants, buttocks implants, lipimplants and other facial implants. Implantable medical devices can becoated, at least partially, with the open celled foams described herein.The implantable medical devices can include, but are not limited to,pacemaker leads, stents, stent grafts, implantable pumps, implantablepump systems, gastric band devices, access ports, heart valves,implantable tubing, and the like. The implant can in some embodiments beany implant that is located adjacent to muscle tissue.

The opened celled foams themselves can be formed of substantially puresilicone and generally comprise a highly interconnected matrix ofspheres. For example, the “substantially pure” foams can include greaterthan about 50% silicone, greater than about 75% silicone, greater thanabout 90% silicone, greater than about 95% silicone or greater thanabout 99% silicone. The remaining component can be comprised of fusedsilica, other elastomers, thermoplastics or thermosets, ceramics metals,metal alloys or composites thereof.

In some embodiments, a portion of the spheres are hollow. For example,less than about 1% of the spheres are hollow, less than about 5% of thespheres are hollow, less than about 10% of the spheres are hollow orless than about 25% of the spheres are hollow. The percentage of hollowspheres will be dependent on the processes used to make the open celledfoam.

The matrix of interconnected spheres making up the open celled foamsdescribed herein can have an associated void space within them. Atheoretical void space can be a calculated void space that is dependenton the composition of the spheres themselves and the leachable agent,for example. Theoretical void space is a term of art that is wellunderstood by those of skill in the art, and in the context of thepresent disclosure can be generally defined as the percentage by volumeof the foam occupied by the leachable agent on a dry basis. Thetheoretical void space can be greater than about 50% of the foam,greater than about 75% of the foam greater than about 90% of the foam,greater than about 95% of the foam or greater than about 99% of thefoams. In some embodiments, the theoretical void space can be about 50%to about 99% of the foam or about 60% to about 88% of the foams.

Once the open celled foams have been cured and leachable agents removed,the foams have a characteristic actual or physical void space betweenthe matrix of interconnected microspheres. This physical void space canbe greater than about 30%, greater than about 40%, greater than about50%, greater than about 60% or even as much as 70%. Ranges of boththeoretical and physical void space including the percentages describedare within the scope of the present description.

Tissue ingrowth occurs into the voids within the foam when the opencelled foams described herein are used to coat an implantable medicaldevice, such as a soft tissue implant. The ingrowth of tissue isintended to promote the disorganization of collagen fibers, but may beused to increase the surface area of the implant-tissue interface forexample for potential drug delivery, increased cellular proliferation(e.g. tissue bulking) or any other application.

The physical void space of the open celled foams described herein may,in some embodiments, be different than the theoretical void space. Inpractice, starting with a theoretical void space, may not translate intoan actual void space because of factors such as phase separation,settling effects, solvent evaporation, capsule formation in the siliconein place of spheres, and the like.

The silicone used to form the open celled foams, also termed the matrixagent, can be any biocompatible silicone known in the art. The matrixagent can be a RTV silicone, HTV silicone, an acetoxy, oxime or platinumcuring system or other silicone system. In one embodiment, the siliconeis room temperature vulcanizing (RTV) silicone. In another embodiment,the silicone is high temperature vulcanizing (HTV) silicone.

The interconnected spheres making up the matrix of the foams describedherein have diameters between about 10 μm and about 2,000 μm, betweenabout 1 μm and about 500 μm, between about 10 μm and about 250 μm,between about 25 μm and about 200 μm, or between about 50 μm and about100 μm.

In one embodiment, open celled foams described herein can be formed byan emulsion process. The process involves combining two compositions inthe form of solutions, mixtures, suspensions or emulsions. In oneembodiment, two solutions are used. The first composition(composition 1) contains one or more solvents and one or moreextractable agents. The second composition (composition 2) contains oneor more solvents and one or more matrix agents. The ratio of thecomposition 1:2 can be varied to obtain the optimal results; the totaldissolved solids in each composition may be varied to obtain the optimalresults, and the starting component temperatures can be varied to obtainoptimal results.

The compositions are then combined, agitated to produce an emulsion ormixture and cast or injected into flat moulds for curing. It will beappreciated by those skilled in the art that the materials in theiremulsified form can be used in any end processing application that canbe envisioned by a person skilled in the art of coating, lamination orgeneral material or device fabrication. Heat can be optionally appliedto the system for curing, or the system may be left to dry at roomtemperature. Further, the system can be subjected to a vacuum prior tothe application of heat. After the removal of the leachable agent(s) byheat and/or vacuum and/or dissolution and/or sublimation, the resultingmatrix material is considered cured. If the resulting matrix materialcannot maintain its shape without the leachable agent(s), the curing canhappen during or before the removal of the leachable agent. Theresulting product is an open celled foam.

The emulsion process can be considered a phase inversion process becausethe two compositions are mixed in a manner which creates a phaseinverted emulsion (with respect to a continuous phase of silicone)wherein the silicone phase is in the spherical shape and the leachablephase in the continuous shape. Without wishing to be bound by anyparticular theory, it is believed that because silicone oils have verylow surface tension (high cohesivity in liquid form), it is necessary todecrease the silicone content in the final solution mix in order tocreate the phase inversion. As the phase inversion occurs, the siliconeis in the sphere form and the leachable portion is in the matrix form.However, because of the low surface tension of silicone and its uniqueability to readily wet surfaces (as well as high cohesivity), as theemulsion dries and cures, the resulting silicone microspheres becomeattached to one another thereby forming a network of interconnectedspheres. The final form of the material is a solid sheet with amicrosphere matrix microstructure.

A surprising feature of the open celled foams described herein is theratio of total solids. The silicone is in the minority phase compared tothe leachable phase. As a result of silicone and its corresponding oilshaving very low surface tensions, on the order of 21.5 mN/m for a >300cst fluid, they are very prone to readily wet clean surfaces (forcomparative purposes water is 71.97 mN/m at 25° C.). Silicones abilityto fully wet most surfaces prevents the use of standard porogens (suchas salt sugar or standard emulsions) as matrices for creating astructure that is open enough to be biocompatible and sufficiently opento disorganize the surrounding tissues for the application of preventingor reducing the frequency of capsular contracture. The present opencelled foams utilize phase inversion of the emulsion to createinterconnections. It has been observed that until phase inversion of theemulsion occurs, the cells of the final foam remain closed. Furthermore,if the emulsion is too dilute, the material falls apart as microspheres.A surprising result of the present foams is that the material fallsapart at much lower concentrations of total dissolved solids andmatrix/leachable v/v ratios as compared to most conventional materialsprepared using this method.

The highly interconnected soft structure of the opened celled foamsdescribed herein creates the optimal geometry for preventing classicalcapsular formation around a soft tissue implant. For example, one canconstruct a set of binary phase diagram with a two component system foreach particular configuration of solvent ratios. In such a system, asillustrated in FIG. 1, a desired range can be selected where the matrixagent, or non-leachable component, forms microspheres which are adherentto each other and thereby form a stable structure when the leachablecomponent or agent is extracted. At concentrations of a leachable agentwhich exceed the desired concentration the material will fall apart asmicrospheres after the leachable agent is extracted. Conversely, atconcentrations where the leachable agent is at lower than desiredconcentrations a closed cell foam will be created. An individual skilledin the art can envisage such phase diagrams for different materials withappropriate surface tension properties.

In one embodiment described herein are implantable composite membershaving an external surface at least a portion of which is covered by anopen celled foam as described herein. The implantable composite membersare made by first providing an implantable shell and providing an opencelled foam comprising a matrix of interconnected spheres, the spherescomprising substantially pure silicone, and wherein the matrix ofinterconnected spheres has a void space of about 50% to about 99%. Next,a bonding substance is applied to the open celled foam thereby forming abondable open celled foam. The bonding substance will act as a means forattaching the open celled foam to the implantable shell. The bondableopen celled foam is then applied to at least a portion of theimplantable shell and the bonding substance is cured. Alternatively thebonding agent can be applied directly to the device, and not to the opencelled foam. The curing of the bonding substance adheres the open celledfoam to the implantable shell thereby forming a composite materialhaving an external surface at least a portion of which is covered by anopen celled foam.

In some embodiments, the bonding substance is room temperaturevulcanizing silicone (RTV) or high temperature vulcanizing (HTV)silicone. The bonding substance can be applied to the open celled foamsusing any method known in the art, for example, brushing, spraying,dipping, curtain coating, vapor deposition methods can be used, castingmethods can be used, injection molding and the like. The bondingsubstance can be cured using heat or any other means of aiding in curingknown in the art.

After the open celled foam has been adhered to the surface of theimplantable shell, extra portions of foam can be trimmed off to make arelatively smooth edge. In some embodiments, the process is termedlamination.

Open celled foams as described herein can be laminated onto a smoothimplant shell using silicone adhesive. The lamination step can be donewhile the implant is still on the mandrel or on finished implant. Thelamination process can utilize a two piece cavity in which a finishedsmooth implant is pressed between two open celled silicone foam sheets.

For example, the foams can be laminated onto finished smooth implants. Adispersion of HTV silicone is used as the adhesive between the implantand the foam sheets. In the process, the first foam sheet is coated witha thin layer of HTV silicone and then placed in the bottom cavity. Thesmooth implant is then placed on top of the foam sheet in the cavity.The second foam sheet is coated with a thin layer of HTV silicone andapplied on top of the smooth implant. The top piece of the cavity isthen fixed in place pressing the two foam sheets together creating auniform interface. The silicone adhesive is allowed to cure and then theexcess foam is cut off creating a uniform seam around the implant.

Another exemplary process involves laminating the foam onto a smoothimplant still on a mandrel. In this process a HTV silicone is used asthe adhesive between the implant and the foam sheets. The first foamsheet is coated with a thin layer of HTV silicone and then draped overthe smooth implant on the mandrel in such a way that there are nowrinkles on the top surface. After this has cured, another coating ofHTV silicone is applied and the foam is stretched up to cover part ofthe back of the implant. The smooth implant is then taken off themandrel and the excess foam is removed. A smaller circle is cut out of afoam sheet to fit the back of the implant. A thin layer of HTV siliconeis applied to the small circle of foam and the circle is attached andallowed to cure.

In another embodiment, a bonding surface is applied to the implant bydipping the implant into HTV silicone and then lamination of the foamonto the implant. The HTV silicone can be applied to the implant usingany technique known to those skilled in the art, for example, byspraying curtain coating, and the like.

In yet another embodiment, the implantable shell is coated with anemulsion including an agitated mixture of a first organic solvent and atleast one extractable agent, and a second organic solvent and at leastone silicone matrix agent. The emulsion can also be applied to theimplantable shell. A common method used to coat an implantable shell isto first form the shell itself on a mandrel using a dipping techniqueand then after the shell is formed, to dip that formed shell into acomposition as described herein. The emulsion is then allowed to cure onthe implantable shell thereby forming the open celled foam. Extractablematerials can then be removed from the open celled foam using variousdrying and/or leaching techniques known in the art. In one exampleembodiment, the curing step optionally includes heating.

If the open celled foam is formed on the implantable shell itself, thestep of coating and/or applying the emulsion to the implantable shell isaccomplished using any method known in the art. For example, spraying,dipping, vapor deposition, brushing, and the like can be used. In anexemplary embodiment, the implantable shell is dipped into an agitatedemulsion.

In some embodiments, the open celled foams can be applied only toportions of the implantable shell. For example, only the front of theshell is be coated, or only the back of the shell is be coated, or onlyabout 20%, about 30%, about 40%, about 50%, about 60%, about 70% about80% or about 90% of the shell is coated. In other embodiments,substantially all of the shell is coated.

In one embodiment, the implantable shell is a silicone based shellsuitable for use in the manufacture of breast prosthesis or othercomposite members. The breast prosthesis can be any breast implant knownin the art. After applying an open celled foam to a breast prosthesis asdescribed herein, the steps required to make a finished prosthesis maybe conventional. First, the opening left by the supporting mandrel ispatched with uncured silicone elastomer sheeting. If the prosthesis isto be filled with silicone gel, this gel is added and cured, the filledprosthesis packaged, and the packaged prosthesis sterilized. If theprosthesis is to be inflated with a saline solution, a valve isassembled and installed, the prosthesis is post cured if required, andthe prosthesis is then cleaned, packaged and sterilized. A combinationsilicone/saline mammary prosthesis can also be made.

In other embodiments, the implant can be a pace maker lead, a medicalport, catheter, dura mater substitutes, hernia meshes or the like.

The extractable agent, or removable polymer may be, for example, a watersoluble material dispersed throughout the curable elastomer. Typicalextractable agents or leachable materials may comprise, for example,polyethylene glycol (PEG, also known as polyoxyethylene), polyalkyleneoxides including polyethylene oxide and polyethylene oxide/polypropyleneoxide copolymers (also known as poloxamers),polyhydroxyethylmethacrylate, polyvinylpyrrolidone, polyacrylamide, orother substituted polyolefins and their copolymers, polylactides,polyglycolides, or other polyesters, polyanhydrides, polyorthoesters andtheir copolymers, proteins including albumin, peptides, liposomes,cationic lipids, ionic or nonionic detergents, salts including potassiumchloride, sodium chloride and calcium chloride, sugars includinggalactose, glucose and sucrose, polysaccharides including solublecelluloses, heparin, cyclodextrins and dextran, and blends of the same.

When an extractable agent such as PEG is used, the molecular weight ofthe PEG can be influential on the way the emulsion forms. For example,in one embodiment, the PEG (monomethyl) polymer has a molecular weightof about 2,000 Da. In another embodiment, the PEG polymer has amolecular weight greater than about 750 Da. In some embodiments, the PEGmolecular weight ranges from about 1,000 Da to about 100,000,000 Da, ormore preferably about 1,000 Da to about 10,000 Da.

In some embodiments, the extractable agent is an agent selected from thegroup of agents consisting of polyvinly alcohol, polyethylene glycol,polyethylene oxide, polyacrylic acid; polymethacrylate, poly-lactide,polyglycolide, polycaprolactone, polydioxanone, derivatives thereof,blends thereof, copolymers thereof, terpolymers thereof, andcombinations thereof or other biodegradable or non-biodegradablepolymers, metals ceramics, composites, or combinations thereof.

The solvent component of the composition can include a solvent selectedfrom the group consisting of xylene, pentane, hexane, dichloromethane(DCM), dimethyl sulfoxide, dioxane, NMP, DMAc, and combinations thereofor any other protic or aprotic solvent or combinations thereof.

The presently described open celled foams comprising matrices ofinterconnected spheres provide soft tissue implants with the ability fortissue ingrowth into the voids within the foams once implanted. Thistissue ingrowth prevents or substantially prevents the formation of acapsule around the soft tissue implant. Hence, contracture of a capsuleformed around a soft tissue implant and associated bleeding is avoidedusing the open celled foams described herein. Thus, implants comprisingthe open celled foams described herein may provide relief fromcontracture pain from capsules surrounding the implants.

A method has been described for creating a foam outer layer having anopen-cell structure on, for example, a silicone member. Further, themethod can be applied to create a medical implant with an externalsurface layer of silicone foam having an open-cell structure for use increating strips having a textured surface for control of scar formation,or to improve a process for making mammary prostheses. The product madeby this method has utility in preventing capsular contraction, inpreventing or controlling scar formation, and in anchoring medicalimplants.

Scar tissue formation in the healing of a wound or surgical incision isalso a process involving the growth of fibrous tissue. A visible scarresults from this healing process because the fibrous tissue is alignedin one direction. However, it is often aesthetically desirable toprevent or significantly reduce classical scar formation, especially incertain types of plastic surgery. A member having an open-cell structuresurface made in accordance with the present invention can be placedsubcutaneously within a healing wound or incision to prevent the fibroustissue from aligning and thereby prevent or reduce scar formation.

Even further, it is often important to anchor medical implants toprevent their movement, displacement or rotation. Mammary prostheses areone example of implants that are preferentially anchored. Facialimplants are another example of implants that can be anchored. Withfacial implants, for example, it is important that they be anchoredsecurely against movement because of their prominent location. Providingsuch implants with an open-cell structure surface made in accordancewith the present description is an advantageous way to ensure that theywill be anchored securely as tissue ingrowth once implanted will preventtheir migration.

Example 1 Formulation of Open Celled Foams

Table 1 tabulates data for open celled foams prepared according to themethods of the present description. The open celled foams are created assheets. The formulation components and targets for optimization weretotal dissolved solids (TDS) in the matrix agent and in the extractableagent solution. TDS upon mixing (e.g. in the emulsion phase), which ishighly correlated to viscosity, is important in stabilizing theemulsion. If the TDS are too low, the emulsion is unstable or themicro-geometrically to fine. If the TDS are too high, the emulsioncannot be created without extremely vigorous agitation and/or themicro-geometry is too coarse. Viscosity has its own implications incoating, casting and the like which are known to those skilled in theart. Also important are the ratio of solution 1 to solution 2 and theratio of the matrix and extractable agents once in solid form. Theformer is important for affecting surface tension between the phases forproper microstructure formation in the emulsion process, the latter isimportant for creating the open celled foam structure. This ratio alsoplays a key role in phase separation of the emulsion.

TABLE 1 Extractable Matrix Solvent A/ Theoretical Total Dissolved NameAgent Agent Solvent B Ratio Void Space Solvents (%) F8 40% PEG 40%DCM/Xylene 1:2 33.33 40 RTV F28 40% PEG 40% DCM/Xylene 1:1 50 40 RTV F3040% PEG 40% DCM/Xylene 3:2 60 40 RTV F31 40% PEG 40% DCM/Xylene 2:166.67 40 RTV F33 40% PEG 40% DCM/Xylene 3:1 75 40 RTV F34 40% PEG 40%DCM/Xylene 4:1 80 40 RTV F35 60% PEG 40% DCM/Xylene 1:1 60 50 RTV F3660% PEG 40% DCM/Xylene 2:1 75 53.33 RTV F38 40% PEG 30% DCM/Xylene 2:172.72 36.67 RTV F39 60% PEG 30% DCM/Xylene 1:1 66.67 45 RTV F40 60% PEG30% DCM/Xylene 2:1 80 50 RTV F41 60% PEG 40% DCM/Xylene 3:1 81.81 55 RTVF42 60% PEG 25% DCM/Xylene 3:1 87.80 51.25 RTV F43 60% PEG 25%DCM/Xylene 4:1 90.56 53 RTV FPV4 4% PVA 25% H₂O/Xylene 1:1 13.8 14.5 RTVFPV5 4% PVA 25% H₂O/Xylene 2:1 24.24 11 RTV FPV6 4% PVA 25% H₂O/Xylene1:2 7.41 18 RTV FPV7 6% PVA 25% H₂O/Xylene 1:1 19.35 15.50 RTV FPV8 6%PVA 25% H₂O/Xylene 2:1 32.43 12.33 RTV FPV9 6% PVA 25% H₂O/Xylene 1:210.71 18.67 RTV FPV12 2% PVA 40% H₂O/Xylene 1:2 2.44 27.33 RTV FPV13 4%PVA 40% H₂O/Xylene 1:1 9.09 22 RTV FPV15 4% PVA 40% H₂O/Xylene 1:2 4.7628.00 RTV FPV16 6% PVA 40% H₂O/Xylene 1:1 13.04 23 RTV FPV18 6% PVA 40%H₂O/Xylene 1:2 6.98 28.67 RTV FPVA4 4% PVA 25% H₂O/DCM 1:1 13.79 14.50RTV FPVA7 6% PVA 25% H₂O/DCM 1:1 19.35 15.5 RTV

Example 2 Formation of an Open Celled Foam

Foam F35 from Table 1 has a theoretical void space of 60% and isprepared using a 1:1 ratio of 60% polyethylene glycol monomethyl ether(PEG) by weight in dichloromethane and 40% MED-1037 adhesive silicone byweight in xylene. The silicone and PEG dispersions are mixed at equalvolumes and vigorously shaken by hand for 30 seconds. They are thenimmediately poured into the desired mold. The volume prepared forcasting is varied depending on the size of the mold to obtain foams ofvarying thicknesses. A standard preparation of this formulation would be200 mL into a 415 cm² circular mold to produce a 2 mm thick foam.

Example 3 Formation of an Additional Open Celled Foam

Foam F41 from Table 1 has a theoretical void space of 81.81% and isprepared using a 3:1 ratio of 60% PEG by weight in dichloromethane and40% MED-1037 adhesive silicone by weight in xylene. The silicone and PEGdispersions are mixed at the ratio of 3 parts PEG to 1 part silicone andvigorously shaken by hand for 30 seconds. They are then immediatelypoured into the desired mold. A standard preparation of this formulationwould be 200 mL into a 415 cm² circular mold to produce a 2 mm foam.

Example 4 Formation of an Additional Open Celled Foam

Foam F42 from Table 1 has a theoretical void space of 87.8% and isprepared using a 1:1 ratio of 60% PEG by weight in dichloromethane and25% MED-1037 adhesive silicone by weight in xylene. The silicone and PEGdispersions are mixed at the ratio of 3 parts PEG to 1 part silicone andvigorously shaken by hand for 30 seconds. They are then immediatelypoured into the desired mold. A standard preparation of this formulationwould be 400 mL into a 415 cm² circular mold to produce a 2 mm foam.

Example 5 Histological Studies

A smooth disk-shaped implant without a coating is implanted in a rat.FIG. 2 illustrates a typical capsule formed after implantation of smoothdisk 200. At the top left corner of FIG. 2, a small amount ofdisorganized fascia 202 is identifiable, separated by white blobs 204which are fat cells. Right below the fat cells, is located organizedforeign body capsule 206 (organized meaning that the collagen fibers arewell aligned with the biomaterial plane at the bottom right half of FIG.2).

In another example, a smooth implant without a coating at 6 weeks (1.5months) in rat is illustrated in FIG. 3. Clearly visible is panniculuscarnosus muscle top 300, followed by loose disorganized connectivetissue 302 (nonpathological) followed by organized foreign body capsule304 and smooth implant 306. Organized foreign body capsule 304completely surrounds smooth implant 306.

In a further example, FIG. 4 illustrates a multilayer porous implantwith large pores and small interconnections which are not abundantenough to allow substantial tissue ingrowth into the pores. A slightmotion can disrupt the bridges formed between the implant and the tissueand causes bleeding via the broken blood vessels. Bleeding can beobserved through the presence of erythrocytes (red blood cells), in thetissues. It has been observed that a 5 or 6 fold increase in capsulethickness results when such non-optimally interconnected foams areimplanted. This increase in capsule thickness is likely a result of thecontinuous irritation and resulting inflammation that is present at theimplantation site.

A typical polyurethane foam implant is illustrated under lowmagnification in FIG. 5. From top to bottom is disrupted dermis 500(this is an artifact of histology) followed by the panniculus carnosusmuscle 502, followed by loose connective tissue 504 (fascia), followedby an increase in connective tissue 506 density, followed bypolyurethane implant 508. Polyurethane is also present in the area ofconnective tissue 506, as connective tissue is ingrown into thepolyurethane.

The implant is fully infiltrated with loose connective tissue. However,the observed increase in tissue density at the implant-fascia interfacecan be a potential pathological response, e.g. a capsule, which can beprone to contracture. The tissue density is highly disorganized and theingrowth may make the implant perform better than the smooth or possiblystandard textured materials with respect to capsule formation, but atlater stages, as a result of the biodegradable nature of thepolyurethane foam, a smooth implant remains and the tissue canpotentially revert to a pathological state. The other disadvantage ofthis approach is the fact that polyurethane eventually degrades,releasing a potentially carcinogenic diamines. The other disadvantage isthe fact that degradation of the foam eventually leads to the formationof a predominantly smooth implant surface and the contracture ratesincrease.

An open celled foam coated implant 600 made according to the presentdescription is illustrated in FIG. 6. The open celled foam iscomposition F42 from Table 1. As can be seen in FIG. 6, implant 600includes interconnected silicone 602 and pores 604 associated with theopen celled foam. Also, there is an increase in tissue density aroundthe implant, including loose disorganized fascia 606, and there is atissue density decrease for the tissue that has ingrown into theimplant. No pathological capsule is present. As such, there is nothingpresent that could undergo a contracture similar to that seen onimplants known in the art. The advantages of the present open celledfoams over polyurethane coated implants include, for example, theirnon-degradability, their ability to not generate harmful materialsbecause of degradation and the absence of a tissue density increase,e.g. capsule, around the biomaterial.

Another example open celled foam coated implant 700 made according tothe present description is illustrated in FIG. 7. The open celled foamis composition F35 from Table 1. As can be seen in FIG. 7, implant 700includes interconnected silicone 702 and pores 704 associated with theopen celled foam. Adjacent panniculus carnosus muscle 706 can be seen.Also, there is an increase in tissue density around the implant,including loose disorganized fascia 708. There is a difference indensity/porosity of this composition when compared to that illustratedin FIG. 6, however, there is no capsule formation or visuallyquantifiable increase in collagenous tissue density towards theimplant/tissue interface.

Example 6 Qualitative Studies

Various open celled foams were visualized under a scanning electronmicroscope (SEM). FIGS. 8 and 9 are SEM images of formulation F30 fromTable 1 which illustrate the interconnected network or matrix ofmicrospheres. The void space of the foam is clearly visible. FIGS. 10and 11 are SEM images of formulation F31 form Table 1 which illustratethe interconnected network or matrix of microspheres. Again, the voidspace of the foam is clearly visible. FIGS. 12, 13 and 14 are SEM images(middle, bottom and top respectively) of formulation F35 form Table 1which illustrate the interconnected network or matrix of microspheres.The microspheres here are a bit less defined, but a matrix ofinterconnected spheres is still formed. Again, the void space of thefoam is clearly visible. FIG. 15 is a SEM image of formulation F42 formTable 1 which illustrates the interconnected network or matrix ofmicrospheres attached to a solid RTV silicone backing. Again, the voidspace of the foam is clearly visible. FIGS. 16 and 17 are SEM images offormulation F36 form Table 1 which illustrate the interconnected networkor matrix of microspheres. FIG. 16 illustrates formulation F36 on asolid RTV silicone backing and FIG. 17 is a cross sectional view. Again,the void space of the foam is clearly visible in both figures.

Example 7 Lamination of a Soft Tissue Implant

This Example describes laminating open celled foams of the presentdescription onto a finished smooth implant. The present process requiresthe use of a two piece cavity. A 40% dispersion of MED-1037 adhesivesilicone by weight in xylene is used as the adhesive between the implantand the foam sheets, for example F31 from Example 2. First, the foamsheet is coated with a thin layer of 40% MED-1037 adhesive silicone andthen placed in the bottom cavity. The smooth implant is then placed ontop of the foam sheet in the bottom cavity. The second foam sheet iscoated with a thin layer of 40% MED-1037 adhesive silicone and appliedon top of the smooth implant. The top piece of the cavity is then fixedin place pressing the two foam sheets together creating a uniforminterface. The silicone adhesive is allowed to cure and then the excessfoam is cut off creating a uniform seam around the implant.

Example 8 Lamination of a Soft Tissue Implant on a Mandrel

Another process involves laminating the foam, for example F31 fromExample 2, onto a smooth implant still on a mandrel. In this process a40% dispersion of MED-1037 adhesive silicone by weight in xylene is usedas the adhesive between the implant and the foam sheets. The first foamsheet is coated with a thin layer of 40% MED-1037 adhesive silicone andthen draped over the smooth implant on the mandrel in such a way thatthere are no wrinkles on the top surface. After this has cured, anothercoating of 40% MED 1037 adhesive silicone is applied and the foam isstretched up to cover part of the back of the implant. The smoothimplant is then taken off the mandrel and the excess foam is removed. Asmaller circle is cut out of a foam sheet to fit the back of theimplant. A thin layer of 40% MED-1037 adhesive silicone is applied tothe small circle of foam and the circle is attached and allowed to cure.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

What is claimed is:
 1. A process for forming an open celled foamsuitable for implantation, the process comprising the steps of:combining a first composition comprising a first organic solvent and atleast one extractable agent, and a second composition comprising asecond organic solvent and at least one silicone matrix agent therebyforming a mixture, wherein said at least one matrix agent is less thanabout 40% of said mixture; agitating said mixture thereby forming anemulsion; and curing said emulsion thereby forming said open celled foamincluding a matrix of interconnected spheres; wherein said siliconematrix agent is a high temperature vulcanizing (HTV) silicone.
 2. Theprocess according to claim 1 wherein said matrix of interconnectedspheres has a theoretical void space of about 50% to about 99%.
 3. Theprocess according to claim 1 wherein said matrix of interconnectedspheres has a physical void space of about 50% to about 70%.
 4. Theprocess according to claim 1 wherein said first organic solvent and saidsecond organic solvent are selected from the group consisting ofdichloromethane, water, xylene, acetone, methanol, methyl acetate,hexane, benzene toluene, and isopropyl alcohol.
 5. The process accordingto claim 1 wherein said at least one extractable agent is a polymerselected from the group consisting of poly siloxane, polyethyleneglycol, polyethylene oxide, polyvinyl alcohol, and combinations thereof.6. The process according to claim 1 wherein said curing step furthercomprises heating said emulsion.
 7. The process according to claim 1further comprising the step of casting said emulsion before said curingstep.
 8. The process according to claim 1 further comprising the step ofdipping an implant into said emulsion before said curing step.
 9. Aprocess for forming an open celled foam suitable for implantation, theprocess comprising the steps of: combining a first compositioncomprising a first organic solvent and at least one extractable agent,and a second composition comprising a second organic solvent and atleast one silicone matrix agent thereby forming a mixture, wherein saidat least one matrix agent is less than about 40% of said mixture;agitating said mixture thereby forming an emulsion; and curing saidemulsion thereby forming said open celled foam including a matrix ofinterconnected spheres; wherein said at least one extractable agent is apolymer selected from the group consisting of poly siloxane,polyethylene glycol, polyethylene oxide, polyvinyl alcohol, andcombinations thereof.
 10. The process according to claim 9 wherein saidmatrix of interconnected spheres has a theoretical void space of about50% to about 99%.
 11. The process according to claim 9 wherein saidmatrix of interconnected spheres has a physical void space of about 50%to about 70%.
 12. The process according to claim 9 wherein said firstorganic solvent and said second organic solvent are selected from thegroup consisting of dichloromethane, water, xylene, acetone, methanol,methyl acetate, hexane, benzene toluene, and isopropyl alcohol.
 13. Theprocess according to claim 9 wherein said silicone matrix agent is aroom temperature vulcanizing silicone (RTV).
 14. The process accordingto claim 9 wherein said curing step further comprises heating saidemulsion.
 15. The process according to claim 9 further comprising thestep of casting said emulsion before said curing step.
 16. The processaccording to claim 9 further comprising the step of dipping an implantinto said emulsion before said curing step.
 17. A process for forming anopen celled foam suitable for implantation, the process comprising thesteps of: combining a first composition comprising a first organicsolvent and at least one extractable agent, and a second compositioncomprising a second organic solvent and at least one silicone matrixagent thereby forming a mixture, wherein said at least one matrix agentis less than about 40% of said mixture; agitating said mixture therebyforming an emulsion; curing said emulsion thereby forming said opencelled foam including a matrix of interconnected spheres; and dipping animplant into said emulsion before said curing step.
 18. The processaccording to claim 17 wherein said matrix of interconnected spheres hasa theoretical void space of about 50% to about 99%.
 19. The processaccording to claim 17 wherein said matrix of interconnected spheres hasa physical void space of about 50% to about 70%.
 20. The processaccording to claim 17 wherein said first organic solvent and said secondorganic solvent are selected from the group consisting ofdichloromethane, water, xylene, acetone, methanol, methyl acetate,hexane, benzene toluene, and isopropyl alcohol.
 21. The processaccording to claim 17 wherein said silicone matrix agent is a roomtemperature vulcanizing silicone (RTV).
 22. The process according toclaim 17 wherein said curing step further comprises heating saidemulsion.